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Review
. 2020 Apr;11(4):239-250.
doi: 10.1007/s13238-019-00683-9. Epub 2020 Jan 6.

Lifting the veil on the keratinocyte contribution to cutaneous nociception

Matthieu Talagas  1   2   3   4 , Nicolas Lebonvallet  5   6 , François Berthod  7 , Laurent Misery  5   8   6
Affiliations
Review

Lifting the veil on the keratinocyte contribution to cutaneous nociception

Matthieu Talagas et al. Protein Cell. 2020 Apr.

Abstract

Cutaneous nociception is essential to prevent individuals from sustaining injuries. According to the conventional point of view, the responses to noxious stimuli are thought to be exclusively initiated by sensory neurons, whose activity would be at most modulated by keratinocytes. However recent studies have demonstrated that epidermal keratinocytes can also act as primary nociceptive transducers as a supplement to sensory neurons. To enlighten our understanding of cutaneous nociception, this review highlights recent and relevant findings on the cellular and molecular elements that underlie the contribution of epidermal keratinocytes as nociceptive modulators and noxious sensors, both under healthy and pathological conditions.

Keywords: TRP; inflammation; keratinocyte; nociception; pain; skin.

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Figures

Figure 1
Figure 1
Intra-epidermal free nerve endings. The epidermis is innervated by sensory neurons that have cell bodies located in the dorsal root ganglia (DRG) and central projections to the spinal cord. Thinly myelinated Aδ-fibres and unmyelinated C-fibres terminate as intra-epidermal free nerve endings that penetrate to the granular layer of the living epidermis. Aδ-fibres convey the fast and well-localized part of the pain message whereas C-fibres convey the slow and poorly localized part of the pain message. Nociceptive C-fibres are classified into peptidergic C-fibres, which terminate mainly in the spinous layer of the epidermis, and into non-peptidergic C-fibres, which end more superficially in the granular layer
Figure 2
Figure 2
Epidermal keratinocytes modulate nociceptive sensory neuron activity. Keratinocytes produce both pro-nociceptive and anti-nociceptive substances, which bind to the intra-epidermal free nerve endings (FNEs) to modulate neuronal activity. (1) Painful cutaneous injury activates nociceptive FNE. (2) Keratinocytes are also exposed to injury. (3) This exposition to injury induces the release of FNE activators by keratinocytes, such as ATP, PGE2, NGF, IL-1β, IL-6, and endothelin-1, which sensitize nociceptive neurons. Endothelin-1 links to endothelin-A receptors (EAR) on sensory neurons (pro-algesic pathway). (4) In return, peptidergic C-fibres release substance P (SP) and CGRP to activate keratinocytes through an amplification loop leading to the neuronal sensitization. (5) Keratinocyte-released endothelin-1 also links to endothelin-B receptors (EBR) on keratinocytes. In response, superficial keratinocytes release β-endorphin, which activates μ- and κ-opioid receptors (OR) in FNEs, and inhibits pain (analgesic pathway)
Figure 3
Figure 3
Epidermal keratinocytes initiate acute pain. Epidermal keratinocytes express functional sensory receptors, such as TRPV1, TRPV3, TRPV4, and mechanoreceptors (not yet identified). Their activation by noxious stimuli causes a calcium-dependant release of neuroactive substances that specifically activate nociceptive sensory neurons to ultimately elicit acute pain. The substance released in response to TRPV4 activation has not been yet identified. TRPV3 and TRPV4 are probably not major noxious thermosensors (Huang et al., 2011)
Figure 4
Figure 4
Epidermal keratinocytes initiate inflammatory pain. Epidermal keratinocytes express functional TRPV3 and TRPV4 activated by noxious heat, inducing the release of neuroactive substances that specifically activate nociceptive sensory neurons to ultimately elicit allodynia and hyperalgesia. TRPV3 can also be activated by farnesyl pyrophosphate. Keratinocyte TRPV1 and Nav overexpression has also been reported in patients suffering from chronic pain, but the functionality has not been evaluated
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References

    1. Abraira VE, Ginty DD. The sensory neurons of touch. Neuron. 2013;79:618–639. - PMC - PubMed
    1. Alessandri-Haber N, Dina OA, Yeh JJ, Parada CA, Reichling DB, Levine JD. Transient receptor potential vanilloid 4 is essential in chemotherapy-induced neuropathic pain in the rat. J Neurosci. 2004;24:4444–4452. - PMC - PubMed
    1. Andersson DA, Gentry C, Moss S, Bevan S. Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress. J Neurosci. 2008;28:2485–2494. - PMC - PubMed
    1. Atoyan R, Shander D, Botchkareva NV. Non-neuronal expression of transient receptor potential type A1 (TRPA1) in human skin. J Investig Dermatol. 2009;129:2312–2315. - PubMed
    1. Bae S, Matsunaga Y, Tanaka Y, Katayama I. Autocrine induction of substance P mRNA and peptide in cultured normal human keratinocytes. Biochem Biophys Res Commun. 1999;263:327–333. - PubMed